Nephron segment

Til tee successive tubule portions contribute to the ASDN the late portion of the distal convoluted tubule, the connecting tubule, and the collecting duct. The recent observation that collecting duct-specific inactivation of aENaC in the mouse kidney does not impair sodium and potassium balance, suggests that the more proximal nephron segments (late distal convoluted tubule, connecting tubule) are mainly important for-achieving sodium and potassium balance. 

Hayward AL, Hinojos GA, Nurowska B, Hewetson A, Sabatini S, et al. 1999. Altered sodium pump alpha and gamma subunit gene expression in nephron segments from hypertensive rats. J Hypertens 17(8) 1081-1087. 

Most of the that is filtered at the glomerulus is reabsorbed by proximal tubules. K+ appearing in the voided urine was secreted by distal and terminal nephron segments (discussed later). 

The thick ascending limb is a major site of salt absorption and a principal locus of action of an important group of diuretics. Approximately 25% of the filtered sodium is reabsorbed by the thick ascending limb of Henle s loop. Sodium transport in this nephron segment is mediated by Na+-K+-2C1 cotransport (Fig. 21.3). This transporter is present only on the apical, or urine, side of the tubule cells. Although K+ is taken up by the transporter, little net K+ reabsorption occurs in the thick ascending limb because much of the absorbed K+... 

The reabsorption of NaCl by the thick ascending limb is not accompanied by water because of the low hydraulic permeability of this nephron segment. Consequently, the tubular fluid becomes dilute as it passes through the thick ascending limbs. This process contributes to normal urinary dilution. Moreover, when Na+ transport in thick ascending limbs is inhibited, urinary dilution will diminish. 

Urinalysis provides a unique opportunity to selectively and non-invasively sample a single target organ by examination of its endproduct. The levels of proteins and small molecules normally filtered, excluded from filtration, secreted or reabsorbed by the tubules can be used as indicators of the functional status of certain nephron segments, while injury can be assessed by examination of cellular enzymes which are preferentially leaked into the urine (Loeb 1998), or proteins which are either upregulated or leaked in circumstances of cellular injury and subsequently appear in the urine. 

For best results in determining the presence and site of nephron damage, a battery of enzymes as opposed to a single biomarker should be examined, especially since the most sensitive assay is highly variable, depending on the toxicant and species. Additionally, since many of the enzymes are not completely specific to a selected nephron segment, use of a battery of tests allows more precise localization of the site of injury (Price 1982). 

Other enzymes (lactate dehydrogenase, LDH, and aspartate aminotransferase, AST) also indicate tubular injury when present in the urine but they cannot be localized to a specific nephron segment. Despite this, LDH is commonly used as a marker for distal tubular injury (Price 1982 Guder and Ross 1984 Clemo 1998). 

The focus of this chapter is threefold (1) to review components of renal physiology contributing to susceptibility to chemically induced nephrotoxicity, (2) to examine current methodologies for assessment of nephrotoxicity, and (3) to provide examples of a few specific nephrotoxicants, emphasizing mechanisms thought to contribute to the unique or selective susceptibility of specific nephron segments to these toxicants. 

Brezis M, Shanley P, Silva P, Spokes K, Lear S, Epstein FH, Rosen S Disparate mechanisms for hypoxic cell injury in different nephron segments. Studies in the isolated perfused rat kidney. J Clin Invest 76 1796-806,1985... 

At present there is still a lack of well characterized and well differentiated cell lines of human origin representative of the different cell-types present in the nephron and the collecting duct system. However, once available, human immortahzed cell tines of defined nephron segment origin will likely provide a welcome alternative to primary cultures for studying cell properties in vitro in a cell-type dependent way. 

Horster M. Primary culture of mammalian nephron epithella requirements for cell outgrowth and proliferation from defined explanted nephron segments. PfIugersArch 382 209-215,1979. 

Kirk KE, Schaefer JA. Water transport and osmoregulation by antidiuretic hormone in terminal nephron segments. ln The kidney physiology and pathophysiology. Seldin DW, Giebisch G (editors). Raven Press, New York 1992 p. 1693-1725. 

There is convincing evidence that the primary biochemical lesion induced by cisplatin in cancer cells is inhibition of DNA synthesis [27, 28]. The inhibition of DNA synthesis is persistent and occurs at much lower doses than that necessary to inhibit RNA and protein synthesis [29]. Cisplatin binds to two sites in DNA [30] inducing DNA inter- and intrastrand as well as DNA-protein crosshnks [30,31]. What relationship such cisplatin DNA-binding has to renal cytotoxicity is unknown. How such a dechne in DNA synthesis throughout the kidney would explain cell-specific necrosis is problematic but at least two explanations might account for such specificify. First, other cells of fhe kidney repair their DNA lesions while those of the pars recta cannot. Studies in cells whose repair processes are deficient show that cisplatin is especially toxic in them [32] making such a possibility hkely. Second, it may be that the levels of the DNA adducts formed in the pars recta cells are lethal while lower levels in other nephron segments are not. Further studies will be necessary to determine the importance of the reduction in DNA synthesis in renal cytotoxicity. 

Figure 1. Scheme of Li transport along different nephron segments. 

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